Aerosol formulations containing P134a and particulate medicament

ABSTRACT

A pharmaceutical formulation comprising (i) one or more particulate medicaments, and (ii) 1,1,1,2-tetrafluoroethane as propellant, which formulation contains less than 0.0001% w/w surfactant based upon the weight of medicament, particulate medicament being present in an amount from 0.005 to 5% w/w relative to the total weight of the formulation and having a particle size of less than 100 microns, with the proviso that said medicament is other than salmeterol, salbutamol, fluticasone propionate, beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof and with the proviso that when said formulation consists of betamethasone, ergotamine tartrate or sodium cromoglycate and 1,1,1,2-tetrafluoroethane the weight to weight ratio of medicament to propellant is other than 69:7900 or 0.866% w/w.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 08/462,558,filed Jun. 5,1995 now U.S. Pat. No. 5,744,123 issued on Apr. 28,1998;which is a continuation of application Ser. No. 08/302,435, filed Sep.9,1994, now abandoned, which is a continuation of application Ser. No.08/094,175, filed Aug. 5, 1993, now abandoned, which is a 371application of PCT/EP92/028109.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to aerosol formulations of use for theadministration of medicaments by inhalation.

The use of aerosols to administer medicaments has been known for severaldecades. Such aerosols generally comprise the medicament, one or morechlorofluorocarbon propellants and either a surfactant or a solvent,such as ethanol. The most commonly used aerosol propellants formedicaments have been propellant 11 (CCl₃ F) and/or propellant 114 (CF₂ClCF₂ Cl) with propellant 12 (CCl₂ F₂). However these propellants arenow believed to provoke the degradation of stratospheric ozone and thereis thus a need to provide aerosol formulations for medicaments whichemploy so called "ozone-friendly" propellants.

A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise fluorocarbons and hydrogen-containingchlorofluorocarbons, and a number of medicinal aerosol formulationsusing such propellant systems are disclosed in, for example. EP 0372777,WO91/04011, WO91/11173, WO91/11495 and WO91/14422. These applicationsare all concerned with the preparation of pressurised aerosols for theadministration of medicaments and seek to overcome the problemsassociated with the use of the new class of propellants, in particularthe problems of stability associated with the pharmaceuticalformulations prepared. The applications all propose the addition of oneor more of adjuvants such as alcohols, alkanes, dimethyl ether,surfactants (including fluorinated and non-fluorinated surfactants,carboxylic acids, polyethoxylates etc) and even conventionalchlorofluorocarbon propellants in small amounts intended to minimizepotential ozone damage.

2. Description of the Prior Art

Thus, for example EP 0372777 requires the use of1,1,1,2-tetrafluoroethane in combination with both a cosolvent havinggreater polarity than 1,1,1,2-tetrafluoroethane (e.g. an alcohol or alower alkane) and a surfactant in order to achieve a stable formulationof a medicament powder. In particular it is noted in the specificationat page 3, line 7 that "it has been found that the use of propellant134a (1,1,1,2-tetrafluoroethane) and drug as a binary mixture or incombination with a conventional surfactant such as sorbitan trioleatedoes not provide formulations having suitable properties for use withpressurised inhalers". Surfactants are generally recognized by thoseskilled in the art to be essential components of aerosol formulations,required not only to reduce aggregation of the medicament but also tolubricate the valve employed, thereby ensuring consistentreproducibility of valve actuation and accuracy of dose dispensed.Whilst WO91/11173, WO91/11495 and WO91/14422 are concerned withformulations comprising an admixture of drug and surfactant, WO91/04011discloses medicinal aerosol formulations in which the particulatemedicaments are pre-coated with surfactant prior to dispersal in1,1,1,2-tetrafluoroethane.

A SUMMARY OF THE INVENTION

We have now surprisingly found that, in contradistinction to theseteachings, it is in fact possible to obtain satisfactory dispersions ofmedicaments in fluorocarbon or hydrogen-containing chlorofluorocarbonpropellants such as 1,1,1,2-tetrafluoroethane without recourse to theuse of any surfactant or cosolvent in the composition, or the necessityto pre-treat the medicament prior to dispersal in the propellant.

There is thus provided in one aspect of the invention a pharmaceuticalaerosol formulation which comprises particulate medicament and afluorocarbon or hydrogen-containing chlorofluorocarbon propellant, whichformulation is substantially free of surfactant and with the provisothat said medicament is other than salmeterol, salbutamol, fluticasonepropionate, beclomethasone dipropionate or a physiologically acceptablesalt or solvate thereof By "substantially free of surfactant" is meantformulations which contain no significant amounts of surfactant, forexample less than 0.0001% by weight of the medicament.

The particle size of the particulate (e.g. micronized) medicament shouldbe such as to permit inhalation of substantially all of the medicamentinto the lungs upon administration of the aerosol formulation and willthus be less than 100 microns, desirably less than 20 microns, andpreferably in the range 1-10 microns, e.g. 1-5 microns.

Medicaments which may be administered in aerosol formulations accordingto the invention include any drug useful in inhalation therapy which maybe presented in a form which is substantially completely insoluble inthe selected propellant. Appropriate medicaments may thus be selectedfrom, for example, analgesics, e.g. codeine, dihydromorphine,ergotamine, fentanyl or morphine; anginal preparations, e.g. diltiazem;antiallergics, e.g. cromoglycate, ketotifen or nedocromil;anti-infectives, e.g. cephalosporins, penicillins, streptomycin,sulphonamides, tetracyclines and pentamidine; antihistamines, e.g.methapyrilene; anti-inflammatories, e.g. flunisolide budesonide,tipredane or triamcinolone acetonide; antitussives, e.g. noscapine;bronchodilators, e.g. ephedrine, adrenaline, fenoterol, fomioterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rirniterol, terbutaline, isoetharine,tulobuterol, orciprenaline, or (-)-4-amino-3,5-dichloro-α- 6-2-(2-pyridinyl)-ethoxy!hexyl!amino!methyl!benzenemethanol; diuretics,e.g. amiloride; anticholinergics e.g. ipratropium, atropine oroxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophyllie, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity and/or stability of the medicament and/or tominimize the solubility of the medicament in the propellant.

Particularly preferred medicaments for administration using aerosolformulations in accordance with the invention include anti-allergics,bronchodilators and anti-inflammatory steroids of use in the treatmentof respiratory disorders such as asthma by inhalation therapy, forexample cromoglycate (e.g. the sodium salt), terbutaline (e.g. thesulphate salt), reproterol (e.g. the hydrochloride salt) or(-)-4-amino-3,5-dichloro-α- 6-2-(2-pyridinyl)-ethoxy!hexyl!amino!methyl!benzenemethanol.

It will be appreciated by those skilled in the art that the aerosolformulations according to the invention may , if desired, contain acombination of two or more active ingredients. Aerosol compositionscontaining two active ingredients (in a conventional propellant system)are known, for example, for the treatment of respiratory disorders suchas asthma. Accordingly the present invention further provides aerosolformulations in accordance with the invention which contain two or moreparticulate medicaments. Medicaments may be selected from suitablecombinations of the medicaments mentioned hereinbefore. Thus, suitablecombinations of bronchodilatory agents include ephedrine andtheophylline, fenoterol and ipratropium, and isoetharine andphenylephrine aerosol formulations.

Preferred aerosol formulations in accordance with the invention comprise(a) an effective amount of a particulate bronchodilatory medicament (b)an effective amount of a particulate antiinflammatory, preferably asteroidal antiinflammatory medicament and (c) a fluorocarbon orhydrogen-containing chlorofluorocarbon propellant with the proviso thatsaid medicaments are other than salmeterol, salbutamol, fluticasonepropionate, beclomethasone dipropionate or a physiologically acceptablesalt or solvate thereof. Alternatively aerosol formulations may containa bronchodilator such as isoprenaline in combination with anantiallergic such as cromoglycate (e.g. the sodium salt). Combinationsof isoprenaline and sodium cromoglycate are especially preferred.

The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

The propellants for use in the invention may be any fluorocarbon orhydrogen-containing chlorofluorocarbon or mixtures thereof having asufficient vapor pressure to render them effective as propellants.Preferably the propellant will be a non-solvent for the medicament.Suitable propellants include, for example, C₁₋₄ hydrogen-containingchlorofluorocarbons such as CH₂ ClF, CClF₂ CHClF, CF₃ CHClF, CHF₂ CClF₂,CHClFCHF₂, CF₃ CH₂ Cl and CClF₂ CH₃, C₁₋₄ hydrogen-containingfluorocarbons such as CHF₂ CHF₂, CF₃ CH₂ F, CHF₂ CH₃ and CF₃ CHFCF₃ ;and perfluorocarbons such as CF₃ CF₃ and CF₃ CF₂ CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of the aboveidentified compounds or mixtures, preferably binary mixtures, with otherfluorocarbons or hydrogen-containing chlorofluorocarbons for exampleCHClF₂, CH₂ F₂ and CF₃ CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄ hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane (CF₃ CH₂ F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃ CHFCF₃).

It is desirable that the formulations of the invention contain nocomponents which may provoke the degradation of stratospheric ozone. Inparticular it is desirable that the formulations are substantially freeof chlorofluorocarbons such as CCl₃ F, CCl₂ F₂ and CF₃ CCl₃.

The propellant may additionally contain a volatile adjuvant such as asaturated hydrocarbon for example propane, n-butane, isobutane, pentaneand isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations which aresubstantially free of volatile adjuvants are preferred.

It is further desirable that the formulations of the invention aresubstantially free of liquid components of higher polarity than thepropellant employed. Polarity may be determined for example, by themethod described in European Patent Application Publication No. 0327777.In particular formulations which are substantially free of alcohols suchas ethanol are preferable. As used herein "substantially free" meansless than 1% w/w based upon the fluorocarbon or hydrogen-containingchlorofluorocarbons in particular less than 0.5% for example 0.1% orless.

A particularly preferred embodiment the invention provides apharmaceutical aerosol formulation consisting essentially of one moreparticulate medicament and one or more fluorocarbon orhydrogen-containing chlorofluorocarbon propellant, with the proviso thatsaid medicament is other than salmeterol, salbutamol, fluticasonepropionate, beclomethasone dipropionate or a physiologically acceptablesalt or solvate thereof.

The formulations of the invention may be prepared by dispersal of themedicament in the selected propellant in an appropriate container, e.g.with the aid of sonication. The process is desirably carried out underanhydrous conditons to obviate any adverse effects of moisture onsuspension stability.

The formulations according to the invention form weakly flocculatedsuspensions on standing but, surprisingly, these suspensions have beenfound to be easily redispersed by mild agitation to provide suspensionswith excellent delivery characteristics suitable for use in pressurisedinhalers, even after prolonged storage. Minimizing and preferablyavoiding the use of formulation excipients e.g. surfactants, cosolventsetc in the aerosol formulations according to the invention is alsoadvantageous since the formulations may be substantially taste and odorfree, less irritant and less toxic than conventional formulations.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The particle size distribution of the aerosol formulations according tothe invention is particularly impressive and may be measured byconventional techniques, for example by cascade impaction or by the"Twin Impinger" analytical process. As used herein reference to the"Twin Impinger" assay means "Determination of the deposition of theemitted dose in pressurised inhalations using apparatus A" as defined inBritish Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Suchtechniques enable the "respirable fraction" of the aerosol formulationsto be calculated. As used herein reference to "respirable fraction"means the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above. The formulations according to the invention have beenfound to have a respirable fraction of 20% or more by weight of themedicament, preferably 25 to 70%, for example 30 to 60%.

Optionally, the medicament may be surface-modified prior to itsdispersion in the propellant by treatment with a substantially non-polarliquid medium which is a non-solvent for the medicament. There is thusprovided in a further aspect of the invention an aerosol formulationcomprising particulate, surface-modified medicament, as defined herein,and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant,which formulation is substantially free of surfactant. By"surface-modified medicament" is meant particles of medicament whichhave been surface-modified by admixture with a substantially non-polarnon-solvent liquid, followed by removal of the liquid, with the provisothat said medicament is other than salmeterol, salbutamol, fluticasonepropionate, beclomethasone dipropionate or a physiologically acceptablesalt or solvate thereof. The substantially non-polar non-solvent liquidmedium is conveniently an aliphatic hydrocarbon, e.g. a lower alkane,which is sufficiently volatile to permit its ready evaporation, e.g. atambient temperature and pressure, after slurrying with the medicament.The use of isopentane as liquid medium is particularly advantageous inthis respect.

The medicament is desirably slurried with- the liquid medium underanhydrous conditions to obviate any adverse effects of moisture onsuspension stability. The slurry may advantageously be sonicated tomaximize the surface-modifying effect of the treatment. The liquid maybe removed by any convenient means for example by evaporation or byfiltration followed by evaporation, provided that following treatmentthe medicament is substantially free of the liquid. The formulations ofthe invention will be substantially free of the non-solvent non-polarliquid. Surface-modified medicament prepared by the above describedprocess comprises a further aspect of the present invention.

The formulations according to the invention may be filled into canisterssuitable for delivering pharmaceutical aerosol formulations. Canistersgenerally comprise a container capable of withstanding the vaporpressure of the propellant used such as a plastic or plastic-coatedglass bottle or preferably a metal can, for example an aluminium canwhich may optionally be anodised, lacquer-coated and/or plastic-coated,which container is closed with a metering valve. The metering valves aredesigned to deliver a metered amount of the formulation per actuationand incorporate a gasket to prevent leakage of propellant through thevalve. The gasket may comprise any suitable elastomeric material such asfor example low density polyethylene, chlorobutyl, black and whitebutadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitablevalves are commercially available from manufacturers well known in theaerosol industry. for example, from Valois, France (e.g. DF10, DF30,DF60), Bespak plc, UK (e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK(e.g. Spraymiser™).

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The particulate medicament is added to acharge vessel and liquified propellant is pressure filled through thecharge vessel into a manufacturing vessel. The drug suspension is mixedbefore recirculation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers aredesigned to deliver a fixed unit dosage of medicament per actuation or"puff", for example in the range of 10 to 5000 microgram medicament perpuff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1, 2, 3 or 4 puffseach time.

Thus, for example, each valve actuation may deliver 5 mg sodiumcromoglycate, 250 microgram terbutaline sulphate or 500 microgramreproterol hydrochloride. Typically each filled canister for use in ametered dose inhaler contains 100, 160 or 240 metered doses or puffs ofmedicament.

The filled canisters and metered dose inhalers described herein comprisefurther aspects of the present invention.

A still further aspect of the present invention comprises a method oftreating respiratory disorders such as, for example, asthma, whichcomprises administration by inhalation of an effective amount of aformulation as herein described.

The following non-limitative Examples serve to illustrate the invention.

EXAMPLE 1

Micronized sodium cromoglycate (1.2 g) is weighed directly into analuminium can and 1,1,1,2-tetrafluorethane (to 18.2 g) added from avacuum flask. A metering valve is crimped into place and the sealed cansonicated for five minutes. The aerosol delivers 5 mg sodiumcromoglycate per actuation.

EXAMPLE 2

Micronized terbutaline sulphate (60 mg) is weighed directly into analuminium can and 1,1,1,2-tetrafluorethane (to 18.2 g) added from avacuum flask. A metering valve is crimped into place and the sealed cansonicated for five minutes. The aerosol delivers 250 microgramterbutaline sulphate per actuation.

EXAMPLE 3

Micronized reproterol hydrochloride (120 mg) is weighed directly into analuminium can and 1,1,1,2-tetrafluorethane (to 18.2 g) added from avacuum flask. A metering valve is crimped into place and the sealed cansonicated for five minutes. The aerosol delivers 500 microgramreproterol hydrochloride per actuation.

EXAMPLE 4

Micronized terbutaline sulphate (60 mg) is weighed directly into analuminium can and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4 g) addedfrom a vacuum flask. A metering valve is crimped into place and thesealed can sonicated for five minutes. The aerosol delivers 250microgram terbutaline sulphate per actuation.

We claim:
 1. A pharmaceutical formulation consisting essentially of (i)one or more particulate medicaments, and (ii) 1,1,1,2-tetrafluoroethaneas propellant, which formulation contains less than 0.0001% w/wsurfactant based upon the weight of medicament, particulate medicamentbeing present in an amount from 0.005 to 5% w/w relative to the totalweight of the formulation and having a particle size of less than 100microns, with the proviso that said medicament is other than salmeterol,salbutamol, fluticasone propionate, beclomethasone dipropionate or aphysiologically acceptable salt or solvate thereof and with the provisothat when said formulation consists of betamethasone, ergotaminetartrate or sodium cromoglycate and 1,1,1,2-tetrafluoroethane the weightto weight ratio of medicament to propellant is other than 69:7900 or0.866% w/w.
 2. A formulation as claimed in claim 1 which is free ofsurfactant.
 3. A formulation as claimed in claim 1 wherein saidmedicament is an anti-allergic, a bronchodilator or an anti-inflammatorysteroid.
 4. A formulation as claimed in claim 1 wherein said medicamentis a bronchodilator.
 5. A formulation as claimed in claim 1 wherein saidmedicament is pirbuterol or a physiologically acceptable salt thereof.6. A formulation as claimed in claim 1 which contains two or moreparticulate medicaments.
 7. A formulation as claimed in claim 1 whichcomprises a particulate bronchodilatory medicament and a particulateanti-inflammatory medicament.
 8. A formulation as claimed in claim 1which comprises a particulate bronchodilatory medicament and aparticulate anti-allergic medicament.
 9. A formulation as claimed inclaim 1 which comprises isoprenaline and cromoglycate or aphysiologically acceptable salt thereof.
 10. A formulation as claimed inclaim 1 which contains 0.01 to 1% w/w of medicament relative to thetotal weight of the formulation.
 11. A formulation as claimed in claim 1which has a respirable fraction of 20% or more by weight of medicament.12. A formulation as claimed in claim 1 wherein said medicament is ananti-allergic medicament selected from the group consisting ofketotifen, nedocromil and physiologically acceptable salts thereof. 13.A formulation as claimed in claim 1 wherein said medicament is ananti-inflammatory medicament selected from the group consisting ofbudesonide and triamcinolone acetonide.
 14. A formulation as claimed inclaim 1 wherein said medicament is an anti-inflammatory medicament whichis flunisolide.
 15. A formulation as claimed in claim 1 wherein saidmedicament is an anti-cholinergic medicament selected from the groupconsisting of ipratropium, atropine, oxitropium and physiologicallyacceptable salts thereof.
 16. A formulation as claimed in claim 1wherein said medicament is a xanthine selected from the group consistingof aminophylline, choline theophyllinate, lysine theophyllinate,theophylline and physiologically acceptable salts thereof.
 17. Aformulation as claimed in claim 1 wherein said medicament iscromoglycate or a physiologically acceptable salt thereof.
 18. Apharmaceutical aerosol formulation consisting of (i) one or moreparticulate medicaments, and (ii) 1,1,1,2-tetrafluoroethane aspropellant, particulate medicament being present in an amount from 0.005to 5% w/w relative to the total weight of the formulation and having aparticle size of less than 100 microns, with the proviso that saidmedicament is other than salmeterol, salbutamol, fluticasone propionate,beclomethasone dipropionate or a physiologically acceptable salt orsolvate thereof and with the proviso that when said formulation consistsof betamethasone, ergotamine tartrate or sodium cromoglycate and1,1,1,2-tetrafluoroethane the weight to weight ratio of medicament topropellant is other than 69:7900 or 0.866% w/w.
 19. A formulation asclaimed in claim 1 wherein said medicament is an anti-allergic, abronchodilator or an anti-inflammatory steroid.
 20. A formulation asclaimed in claim 1 wherein said medicament is a bronchodilator.
 21. Aformulation as claimed in claim 1 wherein said medicament is pirbuterolor a physiologically acceptable salt thereof.
 22. A formulation asclaimed in claim 1 which contains two or more particulate medicaments.23. A formulation as claimed in claim 1 which comprises a particulatebronchodilatory medicament and a particulate anti-inflammatorymedicament.
 24. A formulation as claimed in claim 1 which comprises aparticulate bronchodilatory medicament and a particulate anti-allergicmedicament.
 25. A formulation as claimed in claim 1 which comprisesisoprenaline and cromoglycate or a physiologically acceptable saltthereof.
 26. A formulation as claimed in claim 1 which contains 0.01 to1% w/w of medicament relative to the total weight of the formulation.27. A formulation as claimed in claim 1 which has a respirable fractionof 20% or more by weight of medicament.
 28. A formulation as claimed inclaim 1 wherein said medicament is an anti-allergic medicament selectedfrom the group consisting of ketotifen, nedocromil and physiologicallyacceptable salts thereof.
 29. A formulation as claimed in claim 1wherein said medicament is an anti-inflammatory medicament selected fromthe group consisting of budesonide and triamcinolone acetonide.
 30. Aformulation as claimed in claim 1 wherein said medicament is ananti-inflammatory medicament which is flunisolide.
 31. A formulation asclaimed in claim 1 wherein said medicament is an anti-cholinergicmedicament selected from the group consisting of ipratropium, atropine,oxitropium and physiologically acceptable salts thereof.
 32. Aformulation as claimed in claim 18 wherein said medicament is a xanthineselected from the group consisting of aminophylline, cholinetheophyllinate, lysine theophyllinate, theophylline and physiologicallyacceptable salts thereof.
 33. A pharmaceutical aerosol formulationconsisting essentially of (i) one or more particulate medicaments, and(ii) 1,1,1,2-tetrafluoroethane as propellant, which formulation is freeof surfactant, particulate medicament being present in an amount from0.005 to 5% w/w relative to the total weight of the formulation andhaving a particle size of less than 100 microns, with the proviso thatsaid medicament is other than salmeterol, salbutamol, fluticasonepropionate, beclomethasone dipropionate or a physiologically acceptablesalt or solvate thereof and which formulation contains less than 0.866%w/w of medicament relative to the total weight of the formulation.
 34. Apharmaceutical aerosol formulation consisting essentially of (i) one ormore particulate medicaments, and (ii) 1,1,1,2-tetrafluoroethane aspropellant, which formulation is free of surfactant, particulatemedicament being present in an amount from 0.005 to 5% w/w relative tothe total weight of the formulation and having a particle size of lessthan 100 microns, with the proviso that said medicament is other thansalmeterol, salbutamol, fluticasone propionate, beclomethasonedipropionate or a physiologically acceptable salt of solvate thereof andwhich formulation contains 0.005 to 0.659% w/w medicament relative tothe total weight of the formulation.